Despite increased plasma concentrations of HDL and apoA-I, LCAT transgenic (L-Tg) mice have enhance diet-induced atherosclerosis. In contrast, expression of the same transgene in NZW rabbits results in reduced aortic atherosclerosis. One of the major differences in the HDL metabolism between these two transgenic animal models is a deficiency of cholesteryl ester transfer protein (CETP) in mice. To evaluate whether CETP deficiency modulates the development of atherosclerosis in L-Tg mice we crossed CETP-Tg x L-Tg mice. Compared to L-Tg mice, CETP x L-Tg mice had reduced plasma concentrations of cholesterol, cholesteryl esters, HDL-C and apoE (-44%,-68%, -49% and -57% that of L-Tg; p<0.05). FPLC analysis revealed a marked reduction of apoE-rich HDL1. Despite decreased plasma concentrations of HDL-C, CETP x L-Tg mice had reduced diet-induced aortic atherosclerosis (40% that of L-Tg; p<0.001). Thus, CETP expression reduces HDL heterogeneity and concentrations in L-Tg mice. CETP-mediated transfer of CE from HDL to apoB-containing lipoproteins may normalize L-Tg mouse HDL composition and function, thereby reducing LCAT induced atherosclerosis in mice.